- Exosomes are biogenic nanoscale carriers with low immunogenicity and innate BBB-crossing ability, outperforming synthetic nanocarriers for targeted CNS delivery.
- Intranasal administration provides a non-invasive, direct nose-to-brain route via olfactory and trigeminal nerves, reducing systemic exposure while bypassing the BBB.
- Clinical translation requires GMP scale-up, standardised particle dosing, and large placebo-controlled trials to address manufacturing, regulatory and standardisation hurdles.
Biochem Biophys Res Commun. 2026 Aug 21;834:154474. doi: 10.1016/j.bbrc.2026.154474. Online ahead of print.
ABSTRACT
Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple Sclerosis (MS), represent a substantial and growing global health burden, collectively accounting for millions of disability-adjusted life years (DALYs) worldwide and severely impacting cognition, mood, behavior, and motor function. Current therapies, particularly small-molecule drugs, are challenged by the blood-brain barrier (BBB), resulting in poor central nervous system (CNS) bioavailability, systemic adverse effects, and suboptimal patient adherence, underscoring the urgent need for novel delivery platforms. Exosomes, endogenous nanoscale extracellular vesicles (30-150 nm) derived from sources such as mesenchymal stem cells, neural stem cells, and immune cells, have emerged as highly promising biogenic drug carriers owing to their low immunogenicity, inherent biocompatibility, cargo versatility (proteins, mRNA, miRNA), and unique innate ability to cross the BBB, positioning them as superior alternatives to synthetic nanocarriers such as liposomes, niosomes, and solid lipid nanoparticles for targeted CNS delivery. This review provides a comprehensive overview of exosome biology and therapeutics for AD, PD, and MS, covering classification, isolation and characterization methods, drug-loading strategies and a comparative analysis of administration routes (intravenous, intracerebral, intrathecal, intra-arterial, and intranasal). Particular emphasis is placed on the intranasal route, which offers a non-invasive, direct nose-to-brain pathway via the olfactory and trigeminal nerves, effectively bypassing the BBB while minimizing systemic exposure. The review also examines the dual therapeutic and pathological roles of exosomes in BBB function, and emphasizes preclinical and early clinical evidence across AD, PD, and MS. Finally, the review outlines the major manufacturing, regulatory, and standardization hurdles that must be addressed including GMP-grade scale-up, consistent particle-based dosing benchmarks, and large placebo-controlled trials before intranasal exosome therapeutics can progress from promising preclinical candidates to approved disease-modifying treatments for neurodegenerative disorders.
PMID:42664828 | DOI:10.1016/j.bbrc.2026.154474
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